CN110407763B - Synthesis method of 4- (oxazole-2-yl) benzoic acid - Google Patents
Synthesis method of 4- (oxazole-2-yl) benzoic acid Download PDFInfo
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- CN110407763B CN110407763B CN201910730014.1A CN201910730014A CN110407763B CN 110407763 B CN110407763 B CN 110407763B CN 201910730014 A CN201910730014 A CN 201910730014A CN 110407763 B CN110407763 B CN 110407763B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Abstract
The invention relates to a method for synthesizing 4- (oxazole-2-yl) benzoic acid, which comprises the steps of taking ethanolamine and 4-carboxybenzaldehyde as initial raw materials, firstly synthesizing 4- (4,5-dihydrooxazole-2-yl) benzoic acid, then adding N-bromosuccinimide and azodiisobutyronitrile to obtain 4- (4-bromine-oxazole-2-yl) benzoic acid, and finally carrying out hydrogenation reduction on palladium carbon to obtain 4- (oxazole-2-yl) benzoic acid. Compared with the existing method, the method has the advantages of mild and controllable reaction, good product purity and high yield; meanwhile, the method is good in environmental friendliness and small in influence on the environment; in addition, the method does not need special reagents and equipment, has short synthetic route, high reaction efficiency and low cost, and can be industrially popularized.
Description
Technical Field
The invention relates to the field of drug intermediates, in particular to a synthetic method of 4- (oxazole-2-yl) benzoic acid.
Background
4- (oxazole-2-yl) benzoic acid is widely applied to the fields of dopamine D3 receptor anticaking agents and prostate EP2 receptor anticaking agents as an important chemical or pharmaceutical intermediate, and has important application value (WO 2016130952, CN 106883192).
The synthesis of 4- (oxazol-2-yl) benzoic acid is reported in few ways and is less adaptable to industrial scale-up. The known methods are:
1) Patents WO2012149157 and WO2016067043 report the use of p-cyanobenzoic acid as a starting material which is hydrolyzed with sulfuric acid at 40 ℃ to p-formamidobenzoic acid which is then reacted with 2-bromo-1,1-dimethoxyethane in dioxane for 4 hours to produce 4- (oxazol-2-yl) benzoic acid. The process yields are too low (-3%) and produce large amounts of environmentally unfriendly solid waste, which is not easily industrially scaled up.
2) The synthesis method reported in patent WO2016130952 uses monomethyl terephthalate as raw material, and makes it react with thionyl chloride at 80 deg.C to produce acyl chloride, then reacts with 2-amino-1,1-dimethoxyethane and triethylamine in dichloromethane for 1 hr, then reacts with methanesulfonic acid and phosphorus pentoxide at 140 deg.C to produce 4- (oxazole-2-yl) methyl benzoate, and finally hydrolyzes to produce 4- (oxazole-2-yl) benzoic acid. The method uses a large amount of highly toxic acidic substances such as thionyl chloride, phosphorus pentoxide and the like, and has very high requirements on environment and equipment.
3) The Journal of Organometallic Chemistry,791, 266-273;2015 only reports 4- (4,5-dihydrooxazol-2-yl) benzoic acid, which yields high (-94%), but requires a special ruthenium reagent, which is very costly.
4) The literature Synthesis, (11), 874-4;1989 and European Journal of Organic Chemistry,2018 (4), 515-524;2018 also reports on the synthesis of similar compounds, but it uses bromine on NBS for 4- (4,5-dihydrooxazol-2-yl) benzoic acid and then uses butyl lithium to promote the formation of 2-phenyloxazole, involves the use of the hazardous reagent butyl lithium, and is not suitable for industrial production.
5) Tetrahedron,69 (32), 6591-6597;2013 taking terephthalonitrile and 2-aminoethanol as raw materials, and synthesizing a key intermediate 4- (4,5-dihydrooxazole-2-yl) benzonitrile by using a metal catalyst, or the reaction process is difficult to control, so that the yield is uncontrollable.
6) Patent CN106883192 reports synthesis of 4- (4,5-dihydrooxazol-2-yl) benzonitrile from p-cyanobenzaldehyde and ethanolamine under the catalysis of iodine, oxidation of 4- (oxazol-2-yl) benzonitrile from manganese dioxide and DDQ, and subsequent hydrolysis to obtain 4- (oxazol-2-yl) benzoic acid. Although the method can be industrialized, the solid manganese reagent waste residue generated in the second step oxidation process causes the method to have certain limitations.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a synthetic method for obtaining 4- (oxazole-2-yl) benzoic acid by using ethanolamine and 4-carboxybenzaldehyde as starting raw materials through 3 steps.
In order to achieve the purpose, the invention adopts the technical scheme that: provides a synthesis method of 4- (oxazole-2-yl) benzoic acid, which is characterized in that: synthesizing 4- (4,5-dihydrooxazole-2-yl) benzoic acid by taking ethanolamine and 4-carboxybenzaldehyde as initial raw materials; then brominating and dehydrogenating to obtain 4- (4-bromine-oxazole-2-yl) benzoic acid; finally, hydrogenation reduction is carried out to obtain the 4- (oxazole-2-yl) benzoic acid.
As a preferable scheme, the method specifically comprises the following steps:
(1) 4-carboxybenzaldehyde reacts with ethanolamine to generate 4- (4,5-dihydrooxazole-2-yl) benzoic acid;
(2) Reacting 4- (4,5-dihydrooxazol-2-yl) benzoic acid with azobisisobutyronitrile and N-bromosuccinimide to produce 4- (4-bromo-oxazol-2-yl) benzoic acid;
(3) The 4- (4-bromo-oxazol-2-yl) benzoic acid is reduced by hydrogenation with palladium on carbon to produce 4- (oxazol-2-yl) benzoic acid.
As a more preferable scheme, in the step (1), ethanolamine and boron trifluoride diethyl etherate are sequentially added into 4-carboxybenzaldehyde, the temperature is raised to 40-50 ℃, and the reaction is stirred.
As a more preferable mode, in the step (1), the molar ratio of 2-carboxybenzaldehyde, ethanolamine and boron trifluoride diethyl etherate is 1-5:1-20:0.1-1.
As a more preferable mode, in the step (1), the solvent used in the reaction is acetonitrile.
In a more preferable mode, in the step (2), the N-bromosuccinimide and the azobisisobutyronitrile are added into the 4- (4,5-dihydrooxazole-2-yl) benzoic acid in sequence, and the reaction is stirred at the temperature of 25-30 ℃.
As a more preferred embodiment, in the step (2), the molar ratio of azobisisobutyronitrile, N-bromosuccinimide to 4- (4,5-dihydrooxazol-2-yl) benzoic acid is 0.01: 1.
as a more preferable scheme, in the step (2), the solvent used in the reaction is carbon tetrachloride.
As a more preferable scheme, in the step (3), palladium carbon is added into 4- (4-bromo-oxazol-2-yl) benzoic acid to be reacted under stirring in a hydrogen environment at 25-30 ℃.
As a more preferable mode, in the step (3), the solvent used in the reaction is methanol.
Compared with the prior art, the invention has the beneficial technical effects that: provides a synthesis method of 4- (oxazole-2-yl) benzoic acid; compared with the existing method, the method has the advantages of mild and controllable reaction, good product purity and high yield; meanwhile, the method is good in environmental friendliness and small in influence on the environment; in addition, the method does not need special reagents and equipment, has short synthetic route, high reaction efficiency and low cost, and can be industrially popularized.
Drawings
The invention is further illustrated with reference to the following figures and examples.
Figure 1 is a synthetic scheme for example 1.
FIG. 2 is a nuclear magnetic spectrum of 4- (oxazol-2-yl) benzoic acid, the product of example 1.
Detailed Description
The invention is further described with reference to specific examples. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
Example 1
A synthesis of 4- (oxazole-2-yl) benzoic acid, the synthetic route is shown in figure 1, comprising the following steps:
(1) Synthesis of 4- (4,5-dihydrooxazol-2-yl) benzoic acid:
adding 300 g of 4-carboxybenzaldehyde raw material into 4.5L of acetonitrile, and adding 610 g of ethanolamine into the system at 45 ℃; thereafter, 57 g of boron trifluoride diethyl etherate (content: 46.8%) were added dropwise in portions to the above system. Controlling the temperature to be 45 ℃ and stirring until the reaction is finished, wherein the reaction time is 24 hours; cooling to 30 deg.C, and concentrating under reduced pressure to remove acetonitrile; adding 3 liters of dichloromethane and 3 liters of water, separating liquid, and collecting an organic phase; washing with 1.5L of salt water, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to remove dichloromethane to obtain 325 g of 4- (4,5-dihydrooxazole-2-yl) benzoic acid; yield: 85%, purity: 97 percent.
(2) Synthesis of 4- (4-bromo-oxazol-2-yl) benzoic acid:
325 g of 4- (4,5-dihydrooxazol-2-yl) benzoic acid from step (1) are added to 1.5 l CCl 4 Performing the following steps; 605 g of N-bromosuccinimide (NBS) were added portionwise to the above at room temperature2.8 g of Azobisisobutyronitrile (AIBN) is continuously added after the addition of the materials is finished, and the materials are stirred at 25-30 ℃ until the reaction is completed; distilling under pressure to remove the solvent, adding 3 liters of dichloromethane and 3 liters of water, separating, and collecting an organic phase; drying the mixture by anhydrous sodium sulfate, and concentrating the dried mixture under reduced pressure to remove dichloromethane to obtain 433 g of 4- (4-bromo-oxazol-2-yl) benzoic acid; yield: 95%, purity: 90 percent (the content of dibromo by-product A is 6 percent), and the purity can be directly used in the next step without additional purification when the purity meets the requirement.
(3) Synthesis of 4- (oxazol-2-yl) benzoic acid:
adding 433 g of 4- (4-bromo-oxazol-2-yl) benzoic acid obtained in step (2) to 6 l of methanol; replacing the reaction system with nitrogen for 3 times, adding a reducing agent of palladium carbon (Pd/C) 5 g, and replacing the reaction system with hydrogen for 3 times; keeping the hydrogen pressure at 1 atmosphere, and stirring at 25-3 ℃ until the reaction is complete; suction filtration and reduced pressure concentration are carried out, the obtained crude product is crystallized by dichloromethane/n-heptane, and the white solid product of 223 g of 4- (oxazole-2-yl) benzoic acid is obtained after suction filtration and drying, the yield is as follows: 73%, purity: 99 percent.
Taking the obtained 4- (oxazole-2-yl) benzoic acid as a nuclear magnetic resonance spectrum.
And (3) testing conditions: the type of the spectrogram is a hydrogen spectrum, the testing frequency is 400MHz, and the solvent is deuterated DMSO.
The test results are shown in figure 2, and 4- (oxazole-2-yl) benzoic acid is successfully prepared after 3 steps of reaction.
Example 2
This example is different from example 1 in that:
1. in the step (1), the addition amounts of the ethanolamine and the boron trifluoride diethyl etherate and the corresponding reaction time are different.
2. The addition amounts of the 4- (4,5-dihydrooxazole-2-yl) benzoic acid, the NBS and the AIBN in the step (2) are different; accordingly, the amount of the solvent used in the reaction and the amount of the solvent used in the post-treatment are different.
The method comprises the following specific steps:
(1) Synthesis of 4- (4,5-dihydrooxazol-2-yl) benzoic acid:
adding 300 g of raw material 4-carboxybenzaldehyde into 4.5 l of acetonitrile, and adding 2200 g of ethanolamine into the system at 45 ℃; thereafter 285 g of boron trifluoride etherate (content: 46.8%) were added dropwise in portions to the above system. Controlling the temperature at 45 ℃ and stirring until the reaction is finished, wherein the reaction time is 8 hours; cooling to 30 deg.C, and concentrating under reduced pressure to remove acetonitrile; adding 3 liters of dichloromethane and 3 liters of water, separating liquid and collecting an organic phase; washing once with 1.5L of salt water, drying by anhydrous sodium sulfate, and removing dichloromethane by decompression and concentration to obtain 286 g of 4- (4,5-dihydrooxazole-2-yl) benzoic acid; yield: 75%, purity: and 93 percent.
(2) Synthesis of 4- (4-bromo-oxazol-2-yl) benzoic acid:
5 g of 4- (4,5-dihydrooxazol-2-yl) benzoic acid from step (1) are added to 30 ml of CCl 4 Performing the following steps; adding 30 g of N-bromosuccinimide (NBS) into the system in batches at room temperature, continuously adding 52 mg of Azobisisobutyronitrile (AIBN) after the addition is finished, and stirring at 25-30 ℃ until the reaction is finished; distilling under pressure to remove the solvent, adding 30 ml of dichloromethane and 30 ml of water, separating, and collecting an organic phase; drying with anhydrous sodium sulfate, and concentrating under reduced pressure to remove dichloromethane to obtain 6.9 g of 4- (4-bromo-oxazol-2-yl) benzoic acid; yield: 99%, purity: 86 percent (the content of the dibromo-product A is 8 percent), and the purity can be directly used in the next step without additional purification when the purity meets the requirement.
In light of the foregoing description of the preferred embodiment of the present invention, it is to be understood that various changes and modifications may be made by one skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.
Claims (10)
1. A method for synthesizing 4- (oxazole-2-yl) benzoic acid is characterized in that: synthesizing 4- (4,5-dihydrooxazole-2-yl) benzoic acid by taking ethanolamine and 4-carboxybenzaldehyde as initial raw materials; then brominating and dehydrogenating to obtain 4- (4-bromo-oxazol-2-yl) benzoic acid; finally, hydrogenation reduction is carried out to obtain the 4- (oxazole-2-yl) benzoic acid.
2. The method of synthesizing 4- (oxazol-2-yl) benzoic acid according to claim 1, characterized in that: the method specifically comprises the following steps:
(1) 4-carboxybenzaldehyde reacts with ethanolamine to generate 4- (4,5-dihydrooxazole-2-yl) benzoic acid;
(2) Reacting 4- (4,5-dihydrooxazol-2-yl) benzoic acid with azobisisobutyronitrile and N-bromosuccinimide to generate 4- (4-bromo-oxazol-2-yl) benzoic acid;
(3) The 4- (4-bromo-oxazol-2-yl) benzoic acid is reduced by hydrogenation with palladium on carbon to produce 4- (oxazol-2-yl) benzoic acid.
3. The process for the synthesis of 4- (oxazol-2-yl) benzoic acid according to claim 2, characterized in that: in the step (1), ethanolamine and boron trifluoride diethyl etherate are sequentially added into 4-carboxybenzaldehyde, the temperature is raised to 40-50 ℃, and the mixture is stirred for reaction.
4. The method of synthesizing 4- (oxazol-2-yl) benzoic acid according to claim 3, characterized in that: in the step (1), the molar ratio of the 2-carboxybenzaldehyde to the ethanolamine to the boron trifluoride diethyl etherate is 1-5:1-20:0.1-1.
5. The method of synthesizing 4- (oxazol-2-yl) benzoic acid according to claim 3, characterized in that: in the step (1), the solvent adopted in the reaction is acetonitrile.
6. The process for the synthesis of 4- (oxazol-2-yl) benzoic acid according to claim 2, characterized in that: in the step (2), N-bromosuccinimide and azobisisobutyronitrile are sequentially added into 4- (4,5-dihydrooxazole-2-yl) benzoic acid and stirred for reaction at the temperature of 25-30 ℃.
7. The method of synthesizing 4- (oxazol-2-yl) benzoic acid according to claim 6, characterized in that: in the step (2), the molar ratio of azodiisobutyronitrile to N-bromosuccinimide to 4- (4,5-dihydrooxazol-2-yl) benzoic acid is 0.01-2: 1.
8. the method of synthesizing 4- (oxazol-2-yl) benzoic acid according to claim 6, characterized in that: in the step (2), the solvent adopted in the reaction is carbon tetrachloride.
9. The process for the synthesis of 4- (oxazol-2-yl) benzoic acid according to claim 2, characterized in that: in the step (3), palladium carbon is added into 4- (4-bromo-oxazole-2-yl) benzoic acid, and the mixture is stirred and reacts in a hydrogen environment at the temperature of 25-30 ℃.
10. The method of synthesizing 4- (oxazol-2-yl) benzoic acid according to claim 9, characterized in that: in the step (3), the solvent used in the reaction is methanol.
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| WO2003040096A2 (en) * | 2001-11-08 | 2003-05-15 | Elan Pharmaceuticals, Inc. | N, n'-substituted-1,3-diamino-2-hydroxypropane derivatives |
| CN1759095A (en) * | 2001-11-08 | 2006-04-12 | 艾伦药物公司 | N,N'-substituted-1,3-diamino-2-hydroxypropane derivatives |
| WO2012149157A2 (en) * | 2011-04-26 | 2012-11-01 | Bioenergenix | Heterocyclic compounds for the inhibition of pask |
| WO2017064488A1 (en) * | 2015-10-13 | 2017-04-20 | Indivior Uk Limited | Dopamine d3 receptor antagonists having a morpholine moiety |
| CN106883192A (en) * | 2017-03-30 | 2017-06-23 | 苏州汉德创宏生化科技有限公司 | The synthetic method of the benzoic acid derivative of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification |
| CN107427699A (en) * | 2015-02-12 | 2017-12-01 | 伊美格生物科学公司 | For treating the KDM1A inhibitor of disease |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003040096A2 (en) * | 2001-11-08 | 2003-05-15 | Elan Pharmaceuticals, Inc. | N, n'-substituted-1,3-diamino-2-hydroxypropane derivatives |
| CN1759095A (en) * | 2001-11-08 | 2006-04-12 | 艾伦药物公司 | N,N'-substituted-1,3-diamino-2-hydroxypropane derivatives |
| WO2012149157A2 (en) * | 2011-04-26 | 2012-11-01 | Bioenergenix | Heterocyclic compounds for the inhibition of pask |
| CN107427699A (en) * | 2015-02-12 | 2017-12-01 | 伊美格生物科学公司 | For treating the KDM1A inhibitor of disease |
| WO2017064488A1 (en) * | 2015-10-13 | 2017-04-20 | Indivior Uk Limited | Dopamine d3 receptor antagonists having a morpholine moiety |
| CN106883192A (en) * | 2017-03-30 | 2017-06-23 | 苏州汉德创宏生化科技有限公司 | The synthetic method of the benzoic acid derivative of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification |
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